Project Summary/Abstract Background and preliminary data: Immuno-PET with 89Zr-labeled antibodies is a promising approach for detection, staging, and characterization of malignant tumor. Recently, we have applied this approach to imaging of PDAC using the monoclonal IgG1 antibody HMab-5B1, which potently binds on the cancer antigen (CA) 19-9. Overexpression of CA 19-9 is a well-established feature of PDAC and serum levels of CA 19-9 are commonly used in the clinic for diagnosis, risk stratification, and follow-up of pancreatic cancer. While CA 19-9 enters the circulation, its concentration in the tumor is orders of magnitude higher and leads to accumulation of HuMab-5B1 in the tumor tissue. This has been demonstrated by an ongoing phase I clinical trial at MSK that studies CA 19-9 positive malignancies with 89Zr-DFO-HuMab-5B1 PET/CT. In this trial, 89Zr-DFO-HuMab-5B1 PET/CT has shown not only known metastases, but also many sub-centimeter lesions that were not apparent on routine clinical imaging (CT, MRI). Furthermore, a significant fraction of the patients demonstrated very high and persistant uptake of 89Zr-DFO-HuMab-5B1 in the tumor tissue (SUVmax up to 101 g/ml) and tumor-to- blood ratios were higher than 10 for 50% of the lesions, suggesting that HuMab-5B1 labeled with beta-emitting radioisotopes may deliver therapeutic doses to PDAC. The goal of this application is to validate 89Zr-DFO-HuMab-5B1 PET/CT imaging findings by histopathology in patients with CA 19-9 positive pancreatic cancers scheduled to undergo surgery. Specific aims and approach: We will image 15 patients within one week before surgery and use intraoperative gamma probe measurements to precisely localize these findings in the surgical specimens. The expression of CA 19-9 will be assessed by immunohistochemistry and correlated with the tumor uptake of 89Zr on PET. Patients will undergo a diagnostic CT, optimized for pancreatic cancer imaging as part of the PET/CT study and we will test if the addition of the PET increases the staging accuracy of contrast-enhanced CT. Furthermore, we will perform quantitative autoradiography of the resected specimens in order to quantify the precise concentration of radioactivity in the tumor tissue without interfering partial volume effects. Autoradiography will also allow us to study the intratumoral distribution of 89Zr, which may affect the radiation dose that can be safely administered to the tumor tissue with systematically administered HuMab-5B1 labeled with a therapeutic radioisotope. Impact: If the study confirms our preliminary clinical findings that 89Zr-DFO-HuMab-5B1 PET/CT can detect metastatic PDAC with markedly higher sensitivity than CT alone, this would have a major impact on the selection of patients for surgery and surgical planning. Furthermore, if the degree of uptake of 89Zr-DFO- HuMab-5B1 in PDAC metastases is as high as suggested by our preliminary data, HuMab-5B1 would be a highly attractive theranostic agent for treatment of pancreatic cancer.